2.1 Colorectal Cancer
Colorectal cancer, or cancer of the colon and rectum, is the second leading cause of cancer-related deaths in the United States, and the third most common cancer overall. The American Cancer Society estimates that each year, more than 50,000 Americans die from colorectal cancer and approximately 155,000 new cases are diagnosed, accounting for 15% of all types of tumor. Eighty to 90 million Americans (approximately 25% of the U.S. population) are considered at risk because of age or other factors. More women over the age of 75 die from colorectal cancer than from breast cancer. The 5-year survival rate remains at approximately 45%.
The exact causes of colorectal cancer are unknown, but the disease appears to be caused by both inherited and lifestyle factors. Known predisposing conditions for colorectal cancer include familial adenomatous polyposis (FAP), hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, inflammatory bowel disease, including both chronic ulcerative colitis (UC) and Crohn's disease, family cancer syndromes, and adenomatous polyps (sessile or tubular). In addition, a subset of patients have the propensity to develop flat polyps in the large bowel, particularly in the ascending colon. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. Other risk factors include high-meat, high-fat and low-fiber diets, cigarette smoking, a sedentary lifestyle, and obesity.
Colon cancer can be prevented if the polyps that lead to the cancer are detected and removed. If colon cancer is detected in its early stages, it is up to 90% curable. Fecal occult blood test (annually), sigmoidoscopy (every 5 years), double barium contrast enema (every 5 years), and colonoscopy (every 10 years) are commonly used to screen colorectal cancer. Further, a number of interesting methods such as sucrase-isomaltase now exist to qualitatively determine the degree of dysplasia and allow more precise quantification of individual patient risk for mucosal transformation in inflammatory bowel disease (Wiltz et al., 1991, Gastroenterology 100:1266–78).
Symptoms in patients with colorectal cancer vary depending on the site of the tumor. Circumferential adenocarcinomas of the descending colon, the sigmoid colon, and the mid to upper rectum are the most frequent causes of perturbation in bowel habits, changes in the caliber of the stool, and occasionally—in the more advanced lesions that are close to complete obstruction—paradoxical diarrhea. Other vague symptoms include constipation, blood in the stool, unexplained anemia, abdominal pain and tenderness in the lower abdomen, intestinal obstruction, weight loss with no known reason, stools narrower than usual, constant tiredness, and anal lump. In fact, most colorectal cancer patients display no definitive symptoms.
Squamous cell (epidermoid) carcinomas make up the majority of all primary colorectal cancer. The important subset of cloacogenic (basaloid transitional cell) tumors constitute the remainder. These two histologic variants are associated with human papillomavirus infection. Adenocarcinomas from anal glands or fistulae formation and melanomas are rare.
The staging of colorectal cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
The primary therapy for colorectal cancer remains surgical. Usually, the entire cancer or precancerous lesion is removed and possibly some of the surrounding tissue. More extensive lymphatic or colonic resection, “no touch” techniques, and various regional radiation therapy techniques have largely been touted using anecdotal information or informally designed studies. For patients with mid and distal rectal adenocarcinomas, sphincter preservation approaches have been performed, as well as low anterior approaches with colo-anal reanastomoses. Colonic J pouches and additional physiologic modifications are also options for patients with T1, T2, and perhaps even T3 adenocarcinomas.
For Stages II and III, chemotherapy and/or radiation therapy may be added to help kill the cancer and shrink the tumor. Chemotherapy and radiation may also be used in Stage IV to improve symptoms and prolong life. However, the use of radiation therapy as a single modality in the definitive treatment of colorectal cancer has met with little success despite efforts to increase the total dose to the tumor and reduce the amount of irradiated normal tissue. Radiation therapy is rarely helpful in patients with colorectal cancer that is unsuitable for resection, as the usual reason for nonresectability is the lack of anatomic localization of the cancer. Radiation therapy is sometimes used to relieve localized obstruction, particularly in the region of the cardia, and for patients with chronically bleeding cancers that cannot be resected. The median survival for patients treated with radiation is around 12 months, and long-term survivors are few (Beatty et al., 1979, Cancer 43:2254–67; Newaishy et al., 1982, Clin Radiol. 33:347–352; Schuchman et al., 1980, J Thorac Cardiovasc Surg. 79:67–73).
Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of colorectal cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of colorectal cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include 5-fluorouracil, IMC-C225 (cetuximab), leucovorin, irinotecan, oxaliplatin, Camptosar (Pharmacia & Upjohn), and Celebrex.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkion, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad. Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents, hormone therapy, and radiation are useful in the treatment of colorectal cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.